High-Density Lipoprotein Cholesterol Is a Favorable Prognostic Factor and Negatively Correlated with C-Reactive Protein Level in Non-Small Cell Lung Carcinoma
Background Although the alterations of lipid profile in lung cancer have been documented, the prognostic value of serum HDL-C level and its correlation with inflammation in NSCLC remain unknown. Subjects and Methods Levels of preoperative serum lipid concentrations (including HDL-C, LDL-C, TC, and TG) and the inflammatory biomarker C-reactive protein level (CRP) were retrospectively analyzed in 228 patients with NSCLC and in 300 healthy controls. The serum lipid levels in these two populations were compared. Univariate and multivariate cox hazards analyses were performed to investigate the prognostic value of serum lipid levels in NSCLC. The correlation between CRP and lipid profile were also analyzed. Results Compared with those in normal controls, the serum HDL-C, LDL-C, and TC levels were statistically decreased and the TG levels were significantly increased in 228 NSCLC patients. The patients with decreased levels of HDL-C had significantly lower 5-year survival rates than those with normal HDL-C, not only in the whole NSCLC cohort but also in the subgroups stratified according to the disease T, N classifications, and metastasis, whereas the other lipid components were not independent prognostic factors for NSCLC. Of the lipid components, a lower HDL-C level was observed more often in patients with a high CRP level than in those with a normal CRP level. Spearman’s rank correlation analysis revealed that the HDL-C level presented a negative correlation with the CRP level (r = ?0.360, p<0.001). Conclusions A decreased level of preoperative HDL-C was found to be associated with poor survival in patients with NSCLC. Serum HDL-C level may be a clinical prognosis factor for NSCLC patients. In addition, a negative correlation was present between the levels of HDL-C and CRP, the well-known inflammation biomarker.
References
[1]
Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71–96. doi: 10.3322/ca.2007.0010
[2]
Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, et al. (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18: 581–592. doi: 10.1093/annonc/mdl498
[3]
Brower V (2009) Biomarker studies abound for early detection of lung cancer. J Natl Cancer Inst 101: 11–13. doi: 10.1093/jnci/djn483
[4]
Fiorenza AM, Branchi A, Sommariva D (2000) Serum lipoprotein profile in patients with cancer. A comparison with non-cancer subjects. Int J Clin Lab Res 30: 141–145. doi: 10.1007/s005990070013
[5]
Siemianowicz K, Gminski J, Stajszczyk M, Wojakowski W, Goss M, et al. (2000) Serum HDL cholesterol concentration in patients with squamous cell and small cell lung cancer. Int J Mol Med 6: 307–311. doi: 10.3892/ijmm.6.3.307
[6]
Alexopoulos CG, Blatsios B, Avgerinos A (1987) Serum lipids and lipoprotein disorders in cancer patients. Cancer 60: 3065–3070. doi: 10.1002/1097-0142(19871215)60:12<3065::aid-cncr2820601234>3.0.co;2-q
[7]
Umeki S (1993) Decreases in serum cholesterol levels in advanced lung cancer. Respiration 60: 178–181. doi: 10.1159/000196195
[8]
Moorman PG, Hulka BS, Hiatt RA, Krieger N, Newman B, et al. (1998) Association between high-density lipoprotein cholesterol and breast cancer varies by menopausal status. Cancer Epidemiol Biomarkers Prev 7: 483–488.
[9]
Dessi S, Batetta B, Pulisci D, Spano O, Anchisi C, et al. (1994) Cholesterol content in tumor tissues is inversely associated with high-density lipoprotein cholesterol in serum in patients with gastrointestinal cancer. Cancer 73: 253–258. doi: 10.1002/1097-0142(19940115)73:2<253::aid-cncr2820730204>3.0.co;2-f
[10]
Cruz PM, Mo H, McConathy WJ, Sabnis N, Lacko AG (2013) The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Front Pharmacol 4: 119. doi: 10.3389/fphar.2013.00119
[11]
Irwin ME, Mueller KL, Bohin N, Ge Y, Boerner JL (2011) Lipid raft localization of EGFR alters the response of cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J Cell Physiol 226: 2316–2328. doi: 10.1002/jcp.22570
[12]
Jeon JH, Kim SK, Kim HJ, Chang J, Ahn CM, et al. (2010) Lipid raft modulation inhibits NSCLC cell migration through delocalization of the focal adhesion complex. Lung Cancer 69: 165–171. doi: 10.1016/j.lungcan.2012.06.001
[13]
Ahn J, Lim U, Weinstein SJ, Schatzkin A, Hayes RB, et al. (2009) Prediagnostic total and high-density lipoprotein cholesterol and risk of cancer. Cancer Epidemiol Biomarkers Prev 18: 2814–2821. doi: 10.1158/1055-9965.epi-08-1248
[14]
Kotani K, Sekine Y, Ishikawa S, Ikpot IZ, Suzuki K, et al. (2013) High-density lipoprotein and prostate cancer: an overview. J Epidemiol 23: 313–319. doi: 10.2188/jea.je20130006
[15]
Esteve E, Ricart W, Fernandez-Real JM (2005) Dyslipidemia and inflammation: an evolutionary conserved mechanism. Clin Nutr 24: 16–31. doi: 10.1016/j.clnu.2004.08.004
[16]
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420: 860–867. doi: 10.1038/nature01322
[17]
Mizia-Stec K, Zahorska-Markiewicz B, Mandecki T, Janowska J, Szulc A, et al. (2003) Hyperlipidaemias and serum cytokines in patients with coronary artery disease. Acta Cardiol 58: 9–15. doi: 10.2143/ac.58.1.2005253
[18]
van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, et al. (2002) Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-Plus Study. Diabetes 51: 1088–1092. doi: 10.2337/diabetes.51.4.1088
[19]
Jeppesen J, Hein HO, Suadicani P, Gyntelberg F (1998) Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. Circulation 97: 1029–1036. doi: 10.1161/01.cir.97.11.1029
[20]
Wallberg-Jonsson S, Dahlen G, Johnson O, Olivecrona G, Rantapaa-Dahlqvist S (1996) Lipoprotein lipase in relation to inflammatory activity in rheumatoid arthritis. J Intern Med 240: 373–380. doi: 10.1046/j.1365-2796.1996.53873000.x
[21]
Lim U, Gayles T, Katki HA, Stolzenberg-Solomon R, Weinstein SJ, et al. (2007) Serum high-density lipoprotein cholesterol and risk of non-hodgkin lymphoma. Cancer Res 67: 5569–5574. doi: 10.1158/0008-5472.can-07-0212
[22]
Levy E, Gurbindo C, Lacaille F, Paradis K, Thibault L, et al. (1993) Circulating tumor necrosis factor-alpha levels and lipid abnormalities in patients with cystic fibrosis. Pediatr Res 34: 162–166. doi: 10.1203/00006450-199308000-00011
[23]
Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, et al. (1992) Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 74: 1045–1052. doi: 10.1210/jcem.74.5.1373735
[24]
Cheng X, Li J, Zhang Z (1998) [Analysis of basic data of the study on prevention and treatment of COPD and chronic cor pulmonale]. Zhonghua Jie He He Hu Xi Za Zhi 21: 749–752.
[25]
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, et al. (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol 4: 198–203. doi: 10.1097/01.hco.0000200416.65370.a0
[26]
Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17: 1471–1474. doi: 10.1245/s10434-010-0985-4
[27]
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, et al. (2007) The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2: 706–714. doi: 10.1097/jto.0b013e31812f3c1a
[28]
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106: 3143–3421. doi: 10.1001/jama.285.19.2486
[29]
Ridker PM, Buring JE, Cook NR, Rifai N (2003) C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 107: 391–397. doi: 10.1161/01.cir.0000055014.62083.05
[30]
Kucharska-Newton AM, Rosamond WD, Schroeder JC, McNeill AM, Coresh J, et al. (2008) HDL-cholesterol and the incidence of lung cancer in the Atherosclerosis Risk in Communities (ARIC) study. Lung Cancer 61: 292–300. doi: 10.1016/j.lungcan.2008.01.015
[31]
Guo E, Chen L, Xie Q, Chen J, Tang Z, et al. (2007) Serum HDL-C as a potential biomarker for nodal stages in gastric cancer. Ann Surg Oncol 14: 2528–2534. doi: 10.1245/s10434-007-9401-0
[32]
von Eckardstein A, Hersberger M, Rohrer L (2005) Current understanding of the metabolism and biological actions of HDL. Curr Opin Clin Nutr Metab Care 8: 147–152. doi: 10.1097/00075197-200503000-00007
[33]
Lewis GF, Rader DJ (2005) New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 96: 1221–1232. doi: 10.1161/01.res.0000170946.56981.5c
[34]
Su F, Grijalva V, Navab K, Ganapathy E, Meriwether D, et al. (2012) HDL mimetics inhibit tumor development in both induced and spontaneous mouse models of colon cancer. Mol Cancer Ther 11: 1311–1319. doi: 10.1158/1535-7163.mct-11-0905
[35]
Su F, Kozak KR, Imaizumi S, Gao F, Amneus MW, et al. (2010) Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer. Proc Natl Acad Sci U S A 107: 19997–20002. doi: 10.1073/pnas.1009010107
[36]
Baker M (2004) EGFR inhibitors square off at ASCO. Nat Biotechnol 22: 641. doi: 10.1038/nbt0604-641
[37]
Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R (2005) FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist 10: 461–466. doi: 10.1634/theoncologist.10-7-461
[38]
Giusti RM, Shastri K, Pilaro AM, Fuchs C, Cordoba-Rodriguez R, et al. (2008) U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin Cancer Res 14: 1296–1302. doi: 10.1158/1078-0432.ccr-07-1354
[39]
Italiano A, Besse B, Planchard D, Soria JC (2007) [Targeting epidermal growth factor receptor in non-small cell lung cancer: current advances and perspectives]. Bull Cancer 94: F177–188.
[40]
Gazdar AF (2010) Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev 29: 37–48. doi: 10.1007/s10555-010-9201-z
[41]
Boutsikou E, Kontakiotis T, Zarogoulidis P, Darwiche K, Eleptheriadou E, et al. (2013) Docetaxel-carboplatin in combination with erlotinib and/or bevacizumab in patients with non-small cell lung cancer. Onco Targets Ther 6: 125–134. doi: 10.2147/ott.s42245
[42]
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, et al. (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29: 2866–2874. doi: 10.1200/jco.2010.33.4235
[43]
Engels EA (2008) Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther 8: 605–615. doi: 10.1586/14737140.8.4.605
[44]
Peto R, Darby S, Deo H, Silcocks P, Whitley E, et al. (2000) Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ 321: 323–329. doi: 10.1136/bmj.321.7257.323
[45]
Tietge UJ, Maugeais C, Lund-Katz S, Grass D, deBeer FC, et al. (2002) Human secretory phospholipase A2 mediates decreased plasma levels of HDL cholesterol and apoA-I in response to inflammation in human apoA-I transgenic mice. Arterioscler Thromb Vasc Biol 22: 1213–1218. doi: 10.1161/01.atv.0000023228.90866.29
[46]
Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, et al. (2006) C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol 24: 5216–5222. doi: 10.1200/jco.2006.07.1381
[47]
Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, et al. (2005) The double jeopardy of HDL. Ann Med 37: 173–178. doi: 10.1080/07853890510007322